Silyl acetal tether

One of the best tests for any synthetic methodology is in its application to the preparation of biologically important compounds. Posner et al. recently reported the use of a silyl acetal tether in an IMDA reaction for the preparation of the 2-fIuoroalkyl analog 10 of 1,25-dihydroxy vitamin Dj 11 (Figure 10-5) [8]. 

Scheme 10-68 Preparation of the key silyl acetal tether in one step, during the synthesis of tuni-camycin V.

Scheme 10-81 Formation of the P-1,4-linkage using a silyl acetal tether proved problematic.

Type IIMDA reactions Silicon tethers Silyl acetals... 

The use of silyl acetals as tethering groups in the IMDA reaction is often hampered by the relatively poor yields observed in the formation of unsymmetrical systems. However, the preparation of the triene precursors can be facilitated if only one of the r-systems is linked through a silyl ether connection, while its reacting partner is attached directly to the silicon tether [9]. 

Dialkylvinylsilyl halides are readily prepared, for example, by hydrosilylation of acetylenes indeed, the most simple dimethyl- and diphenylvinylsilyl chlorides are now commercially available. Substitution of the halide with the appropriate hydroxydiene then generates the desired triene precursor. Vinyl silyl ethers are also much more stable than silyl acetals, especially towards hydrolysis nevertheless, a number of mild methods are still available for subsequent removal of the tether. 

The following discussion on the application of the temporary connection to radical cyclizations will be divided into five sections. In the first, a silyl ether is used as the tether in which one of the alkyl groups attached to the silicon possesses the radical precursor (usually a halogen). In the second section, it is the radical acceptor which is introduced on silyl ether formation. The third section concerns the use of silyl acetals as a temporary connection and in the fourth other templating strategies which do not fall into any of the aforementioned areas will be discussed. The final section is a discussion of the use of some of these strategies in C-glycosylation. 

In most cases the radical generated after cyclization is quenched by H-abstraction. However, another possibility is to utilize the cyclized radical in another C-C bond-forming event. Fraser-Reid and co-workers utilized a silyl-tethered radical cyclization of the (L)-rhamnal-derived silyl ether 142 to generate the anomerically. stabilized radical 143, which could be trapped in the presence of an excess of acrylonitrile to generate acetate 144 after tether cleavage and peracetylation (Scheme 10-48) [55a]. This reaction sequence occurred with complete regio- and stereoselectivity. The same group has also used an acetal tether (vide infra) to effect similar transformations [55 b, 56]. 

Silyl acetals have been investigated by Hutchinson and co-workers as tethers in radical cyclization reactions [78]. A number of commercially available dialkyldichlorosilanes were investigated as tether precursors although Pr2SiCl2 was found to be the most suit-... 

Stork and co-workers investigated silyl acetals as the tether-directing group for preparing the difficult )8-mannopyranoside linkage [90]. The desired mixed silyl acetal precursor was initially prepared in a stepwise fashion analogous to that described earlier, by... 

P-Mannopyranosides. Mixed silyl acetals are formed expediently from a cimethylsilyl-tethered sugar unit in which one is mannosyl phenyl sulfoxide. It simply ni olves admixture of two equimolar sugars with 1 equiv. of MCjSiClj in the presence of )MAP and imidazole. The addition of 2,6-di-t-butylpyridine and Tf O at -100° followed warming completes the glycosylation. 

Stork and co-workers investigated the use of silyl acetals as tethers for the stereoselective formation of (3-mannosides [56]. Initial studies were performed on primary acceptors of glucose 57 and mannose. Glucosyl acceptor 57 is first converted to its chlorodimethyl ether derivative by treatment with n-butyllithium... 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

Despite the development of various intermolecular radical addition methods, those studies have rarely accommodated additional functionality, our discovery of the manganese-mediated photolysis conditions notwithstanding. Prior to that discovery, we began to elaborate an alternative strategy which employs temporary tethers ([115, 116] reviews of silicon-tethered reactions [117-120]) (silyl ether or acetal linkages) linking radical and acceptor. In this scenario the C-C bond is constructed via cyclization, in which internal conformational constraints can control diaster-eoselectivity. The tether itself would be converted to useful functionality upon cleavage, and once the tether is cleaved the net result may be considered as formal acyclic stereocontrol. ... 

AUyl propargyl ethers (oxygen-tethered 1,6-enynes) also react intermolecularly with alcohols or water to give six-membered ring acetals or hemiacetals (equation 52) AUyl silyl alkynes react somewhat similarly with Au(I) catalysts in the presence of alcohols to give cyclic or open alkenylsilanes (equation 59). Both types of products are the result of... 

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